Leptomeningeal metastases

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Leptomeningeal metastases are an increasingly recognized problem in advanced cancer that are associated with deterioration and death usually within weeks to a few months. Anatomically, the leptomeninges include the arachnoid and the pia components of the meninges as well as the area between the pia and arachnoid (i.e. the subarachnoid space that contains CSF). Leptomeningeal metastasis occurs when malignant cells spread into the subarachnoid space.


Leptomeningeal metastases are found in 20% of patients who die of advanced cancer at post-mortem; co-existing brain metastases are present in 50% of these patients.

The cancers most likely to cause leptomeningeal metastases include:

  • Breast cancer (especially infiltrating lobular carcinoma)
  • Lung cancer
  • Melanoma
  • Gastrointestinal malignancies
  • Primary brain tumours (e.g. astrocytomas)

Leptomeningeal metastases are occurring more frequently than in previous decades because improved cancer treatment is prolonging life expectancy and the blood-CSF barrier creates a sanctuary site where malignant cells are shielded from chemotherapy.


Tumour can enter the CSF via various mechanisms:

  • Direct infiltration from bony metastases through the dura
  • Via connecting blood vessels
  • Via the nerve sheaths / roots leaving the spinal cord

Malignancy in the leptomeninges can cause:

  • Mass effect either directly, via an inflammatory response or via occlusion of CSF flow with hydrocephalus
  • Cranial nerve or spinal nerve root dysfunction

Clinical Features

Leptomeningeal metastases typically manifest with multifocal neurological symptoms and signs (e.g. diplopia + absent knee reflex).

The most common symptoms and signs include:

  • Headache (40%)
  • Nausea and vomiting (25%)
  • Leg weakness (20%)
  • Cerebellar dysfunction (15%)
  • Altered mental state (15%)
  • Diplopia (15%)
  • Facial weakness (10%)

35% of patients present with symptoms localised to one area (cerebral, posterior fossa or spine), 40% present with features of two areas and 25% present with features of all 3 areas.


Headache is caused by either raised intracranial pressure (associated with morning vomiting and dizziness) or meningeal irritation (e.g. pain and neck stiffness, exacerbated by moving head, pain on straight leg raising).

Altered mental state

Confusion, forgetfulness, disorientation, subtle personality changes, lethargy due to a diffuse cerebral dysfunction or hydrocephalus or seizures occur relatively commonly in leptomeningeal disease. These usually don't occur in isolation but are more commonly associated with another focal sign.

Cranial neuropathies

Diplopia may occur due to cranial nerve III, IV or VI damage.

Facial pain or numbness may occur due to cranial nerve V damage.

Sensorineural hearing loss may occur due to cranial nerve VIII damage.

Dysarthria or hoarsenes due to cranial nerves X and XI damage may occur.

Cerebellar dysfunction

Gait instability, difficulty walking, dizziness and falls may occur due to cerebellar dysfunction.

Radiculopathy and cauda equina compression

When nerve roots are affected by leptomeningeal disease, it is most commonly the nerve roots of the cauda equina that are affected (due to gravity making spread here more likely). Nerve root involvement can result in bowel or bladder dysfunction, leg pain, weakness or numbness, and loss of reflexes.


Partial seizures (sometimes with secondary generalization) occur in up to 25% of patients.


Gadolinium enhanced MRI of the brain and spine is the imaging investigation of choice. The sensitivity of this test is 85%. Findings include thin, diffuse leptomeningeal contrast enhancement or multiple nodular deposits in the subarachnoid space. False positives occur in patients receiving bevacizumab (Avastin).

A lumbar puncture is the gold-standard test. Features include:

  • A high opening pressure (i.e. > 16)
  • Low glucose (CSF:serum ratio < 0.6) (in 30% of cases)
  • High protein (in 80% of cases)
  • Lymphocytic pleocytosis (in 50% of cases)
  • Malignant cells on cytology (in 70% of cases; very high specificity)

Not all of the above lumbar puncture features are usually found, but at least one abnormality is usually present.

Deciding when to investigate for leptomeningeal spread is not always straightforward. A reasonable indication for investigation (with a gadolinium enhanced MRI) is as follows:

  • In patients with unexplained multi-focal neurological symptoms where where investigations are still appropriate either because treatment would be considered or because gaining a diagnosis will help the patient and family

Treatment and Prognosis

In a patient with diagnosed leptomeningeal disease, it is especially relevant to consider these issues:

  • Can neurological function be improved?
  • Is prolonging life important?
  • How will symptoms and quality of life be improved?

Some of the poor prognostic factors that suggest a very short life expectancy include:

  • Low Karnofsky score
  • Fixed neurological deficits
  • Extensive systemic cancer

In patients with the above features, the average life-expectancy is measured in terms of weeks or short months and management should focus on symptom control and comfort care.

On the other hand, life expectancy is longer in patients with the following:

  • Good Karnofsky score (> 60)
  • Minimal systemic disease

In the “better” prognosis patients the median survival is about 3 months, although for breast cancer patients the median survival is significantly longer at 7 months. Some oncologists advocate a more aggressive approach to therapy in the “better” prognosis group of patients and use intrathecal chemotherapy. There is however no evidence to suggest that treatment improves neurological deficit. In a series of 59 patients, no patients had improved neurological deficit at 8 weeks and 75% had deteriorated.



Steroids rarely reverse neurological deficits however they may bring relief in headache and radicular pain.

Opioids and other agents

In addition to steroids for analgesia, opioids and adjuvant agents are indicated for headache and radicular pain.

Ventriculoperitoneal shunting

In patients with hydrocephalus ventriculoperitoneal shunting relieves intractactable headache improving quality of life. It also reduces encephalopathy and incontinence. It is reasonable to consider this in patients who have severe headache despite high dose steroids. A report of 37 patients receiving ventriculoperitoneal shunting found most had substantial relief of symptoms and 1 patient had intracerebral bleeding


Standard anti-emetics are used for nausea. Occasionally nausea and vomiting can be refractory to the more common treatments. Anecdotally, aprepitant can be useful as a last resort for nausea refractory to other anti-emetics.


In addition to their use for radicular pain, anti-convulsants are indicated when seizures occur. Routine prophylaxis is not standard practice except in patients with metastatic melanoma as leptomeningeal spread of melanoma appears to have a very high association with seizures.


The role of radiotherapy is unclear in leptomeningeal disease. It may however relieve symptoms caused by localized leptomeningeal metastases and treatment with 30 Gray over 10 fractions has been shown to help symptomatic locally bulky disease.


Intrathecal (or intraventricular) chemotherapy or systemic chemotherapy that crosses the blood brain barrier may be given in patients for whom aggressive therapy is decided upon. Many systemic agents don't cross the blood barrier, however a few systemic agents do seem to and may be effective (for example gefitinib for EGFR positive non-small cell lung cancer).

Intrathecal methotrexate is a widely used chemotherapy for leptomeningeal metastases. Complications of intrathecal chemotherapy include:

  • Aseptic meningitis
  • Delayed leucoencephalopathy (a few months down the track)
  • Acute encephalopathy
  • Transverse myelitis


Graham Llewellyn Grove